Cushioning wax beads for making solid shaped articles

ABSTRACT

Biologically inactive cushioning beads comprise at least one compressible cushioning component consisting essentially of a microcrystalline hydrocarbon wax or a natural wax, the said wax being at least 30% by weight of the biologically inactive cushioning beads. Such beads are useful for making solid shaped articles containing biologically active ingredients by compression.

The present invention relates to solid, shaped articles, in particulartablets, comprising biologically active substances and to a method forthe production of said articles. It also relates to a mixture of anencapsulated biologically active substance and a plurality of cushioningbeads comprising a specific wax, the said mixture being suitable formaking the solid shaped articles. It further relates to a method ofbiologically treating a mammal or a plant by using such solid shapedarticles.

BACKGROUND OF THE INVENTION

Tablets and capsules are generally unsuitable for administering highdoses of biologically active ingredients since individual large dosageforms are difficult to swallow, or necessitate the administration ofseveral tablets or capsules at a time, leading to impaired patientcompliance. Chewable tablets are not ideal with young children and olderpeople and are furthermore unsuitable for the incorporation ofcontrolled-release coated pellets which can get crushed upon chewing.

Oral liquid suspensions of pharmaceutical and veterinary ingredients aredesigned primarily for those who experience difficulty in swallowingsolid medication. However, they are not suitable for the incorporationof controlled-release particles into aqueous vehicles, since this oftenresults in premature release of the biologically active ingredient intothe suspending media during storage. Various efforts have been made toformulate sustained-release suspensions, the most successful usingion-exchange resins to bind charged molecules. Limitations of thissystem include low drug-loading capability and its applicability to onlyionic drugs.

The formulation of a solid oral dosage form, whether tablet or capsule,which disintegrates rapidly in water to form an instantaneous homogenoussuspension of adequate viscosity to be swallowed could circumvent theproblems of administering large dosages without premature release fromcontrolled-release particles while providing a ready measured dose. Thekey to the development of such a dosage form is a rapidly disintegratingtablet which disperses to form a viscous suspension. A delay in thedevelopment of a viscous gel is essential for achieving disintegrationof the tablet. On the other hand, a rapidly increasing viscosity isnecessary to provide adequate suspension properties.

The ideal solid oral dosage form should contain a swellable materialwhich is able to increase viscosity on contact with water, at least onebiologically active ingredient for immediate or sustained releasedelivery of the biologically active ingredient, and a filler conferringcompactibility and the capability to disintegrate quickly. The inclusionof a viscosity increasing agent as a fine powder in the tablet matrixwithout any processing would interfere with disintegration and result inthe formation of a voluminous hydrophilic mass which is impossible todisperse. Thus, it is necessary to incorporate such an agent into thetablet as granules or spheres so that the disintegration process occursbefore the viscosity increase.

Hard gelatin capsules are well known in the art, especially as apharmaceutical dosage form. Their sizes have been standard since thestart of industrial manufacture their sizes, ranging from 5(corresponding to a volume of 0.13 ml) up to 000 (volume of 1.36 ml).Thus, when a large amount of ingredient is required for each dosageunit, depending on the bulk density of the formulation, it may benecessary to use large size capsules which are not popular by thepatients since thet are too large to swallow or, even worse, a size 000capsule may be too small to receive the said amount. Beads and coatedbeads have often been filled into hard gelatin capsules to be used asconventional or controlled release dosage forms, however it is ratherdifficult to manufacture sustained-release formulations while using ahard gelatin capsule as the dosage form and such attempts have foundrelatively limited use despite efforts to improve the engineering ofsuch formulations. This is why tablets are generally recognized as themost popular pharmaceutical oral dosage form participating in thecomfort of the patient This is especially true of sustained-releasetablets which are designed to release the drug slowly after ingestion Inthis case, patient compliance is improved since the daily number oftablets and the frequency with which the patient has to take thesetablets to obtain the desired effect are considerably reduced. Withsustained-release tablets, the drug's activity can be extended to takeeffect throughout the night, so that the patient need not be awakeneduntil morning, thus resulting in time saving for nurses in hospitals.

The concept of tabletting coated biologically active ingredientparticles is therefore of interest. Attempts have been made to producetablets comprising microcapsules because of the known advantages of thelatter: the microencapsulated substance is protected from externalinfluences and vice-versa, for example stability is increased, chancesof irritations or undesirable reactions with other components in amixture are reduced or eliminated, unpleasant tastes and smells can bemasked. However, compaction of coated beads for making tabletsencounters difficult problems. If the beads have been coated by arate-controlling polymeric cog to sustain biologically active ingredientdelivery, cracking of the coating will cause the delivery system tochange the rate of biologically active ingredient delivery orimmediately release the dose. Preventing cracking of the coating istherefore of utmost importance. Large amounts of carriers have beenfound necessary m most cases in order to overcome the tendency ofmicrocapsules or coated beads to brittleness by preventing their ruptureon compression, thus resulting again in unacceptably large tablets.

The compaction of dry powders consists of two steps: (a) compression ofthe particulate solid followed by (b) bonding of the particles. Thesimplest and most frequent means to study the compaction processinvolves the relationship between punch force and tablet breakingstrength i.e. the force required to break a tablet when subjected to adiametral load. Tablet tensile strength measured by diametralcompression is also an appropriate parameter since it can be related bya simple equation to the applied lead, the tablet diameter and tabletthickness when a cylindrical tablet fails under tension by splittingcleanly into dimetral halves. One of the effects of powder compaction isan increase in the bulk density of the starting material. Quite often,the relationship between the applied pressure and density or porosityappears linear over the normal tabletting range of the applied pressure.

Compaction of shined release tablets containing coated pellets involvesthe following critical aspects. When such a dosage form is developed,the coated pellets must withstand the process of compaction withoutbeing damaged in order to prevent any undesirable effects on thebiologically active ingredient release properties. The type and amountof coating agent, the size of the sub-unit, the selection of externaladditives having a cushioning effect, and the rate and magnitude of theapplied pressure must be carefully considered. The process of beadcompaction involves the application of stress to polymer-coatedspherical cores. The desirable mechanical properties of coated beads tobe compacted into a tablet together with excipients or placebo cushoningbeads should be such that they are strong, not brittle and have lowelastic resilience. The mechanical properties of both uncoated andcoated beads were investigated by Aulton et al, supra who demonstratedthat the presence of a film coat applied by means of an aqueouspolymeric dispersion of polymethacrylates influenced the crushingstrength and the elastic properties of beads: increasing the polymerloading has the effect of increasing the crushing strength of beads,whilst simultaneously enhancing bead resilience (characterized by areduction in the elastic modulus).

Significant changes were observed between the compaction properties ofthe powder and pellet forms of the same formulations: the powderformulations deformed plastically and produced stronger compacts,whereas their pellet forms exhibited elastic deformation and brittlefragmentation, which resulted in compacts of lower tensile strength. Itwas also observed that the biologically active ingredient release ratefrom spheres coated with acrylate polymers increased with an initialincrease in the applied pressure—this being attributed to the cracks inthe coat that formed during compaction—but that further increases inpressure a retarded the release profile, possibly due to closerinter-particulate contacts within the tablet which partly compensatedfor the leaks of the pellet coats.

The selection of external additives is also of importance in the designof tablets since these additives are expected to prevent the occurrenceof film cracking in the coated sub-units. Their compatibility with thebiologically active ingredient-loaded pellets, in terms of particlesize, is also very critical, since a non-uniform size distribution cancause segregation, resulting in tabletting problems such as weightvariation, poor content uniformity, etc. For instance, placebomicrospheres with good “compaction” and “cushioning” properties can beused as diluents. Alternatively, small-size biologically activeingredient-loaded pellets improve the content uniformity of low dosebiologically active ingredients, however the surface area of pellets tobe coated will increase as the size of the pellets deceases.

When using inert “cushioning” beads as diluents, good blending andminimal segregation is essential in order to achieve satisfactoryuniformity of weight and content of the tablet dosage form Segregationis influenced by factors such as markedly different particle size,density or shape. In order to minimize the occurrence of segregationbetween the biologically active ingredient-loaded pellets and the inertdiluent cushioning beads, it is deemed necessary to choose inert beadsof the same size and approximately the same density as the activepellets. Further, the inert cushioning beads should be mechanicallyweaker than the coated biologically active ingredient-loaded ones.

Aulton et al, supra, tried to use different approaches to produce inert“cushioning” beads for cushioning of coated biologically activeingredient-loaded sustained action beads in order to prevent segregationdue to size or density. Inert beads containing high microcrystallinecellulose levels, by virtue of the inherent bonding capacity of thismaterial, were exceedingly hard. In addition, inert beads containinghigh lactose levels were also very hard. The replacement of all or partof the granulating water with isopropyl alcohol (in which lactose wasinsoluble) did not, as expected, enable the preparation of softer inertcushioning beads which would readily Went at low pressure duringtabletting: the resulting beads were still too strong and required threetimes greater applied force than that of the biologically activeingredient-loaded beads before they crush. Thus, it was concluded thatthe admixture of biologically active ingredient-loaded beads and inertbeads was not a viable proposition.

As noted above, conventional highly compactible fillers likemicrocrystalline cellulose can be mixed with biologically activeingredient-loaded beads and compressed into tablets. It is well knownthat beads made from microcrystalline cellulose, alone or in combinationwith brittle materials such as dicalcium phosphate or lactose, are veryhard and not easily deformed or broken. However due to particle sizedifferences with active ingredient-loaded beads, segregation occurs andresults in weight variation and content uniformity problems.Microcrystalline cellulose granules produced by dry or wet granulationtechniques and having similar size as the biologically activeingredient-loaded beads are able to minimize the segregation due to sizedifferences and subsequent problems. However it was noted namely byMillili et al., Drug Dev.Ind.Pharm. 16(8):1411-1426 (1990) and by Aultonet al., Drug Dev.Ind.Pharm. 20(20):3069-3104 (1994) that such advantageis obtained to the detriment of compactibility. Therefore a need remainsfor filler beads which, when used in admixture with biologically activeingredient-loaded coated beads and compressed into tablets, will preventcracking of the coating by keeping a high level of compactibilitywithout giving rise to weight variation and active ingredient contentuniformity problems due to segregation during compacting.

Hereinafter will be given a few specific examples of solutions providedin the prior art in order to attempt solving the various above problems.For instance, British patent No. 1,598,458 discloses successfultabletting of microencapsulated pharmacologically active substanceshaving a brittle coating when a fine powder of a polyethylene glycol oranother water-soluble natural or synthetic wax having a melting pointfrom 30 to 100° C. is used as carrier in an amount from 2 to 20% byweight calculated on the brittle macrocapsules.

A first approach to produce improved tablets containing biologicallyactive ingredient-loaded particles coated with a coating to sustain thebiologically active ingredient action involves the use of flexibleplastically deforming polymeric material which will deform underpressure when forming tablets while maintaining the integrity of thecoating. For instance, EP-A-355,247 discloses that granules of apharmaceutical composition, coated with a primary coating layer andoptionally with a further protective coating, are compressed and moldedtogether with non-coated components containing at least 10% by weight ofnon-swelling polymers having a high degree ofcompressability/moldability and a low degree of desintegrationcharacteristic in order to prevent the destruction of the coating of thecoated granules and to control or modulate the desintegrationcharacteristic of the said coating. The non-swelling polymer may bepolyvinylacetate, polyvinylchloride, polyethylene or an intestinallysoluble polymer such as a cellulose derivative, a styrene-acryliccopolymer or the like. There is no particular limitation or restrictionon the compound used as the coating of the coated granules, which amongothers may be a paraffin, a microcrystalline wax, a higher alcohol, ahigher fatty acid or salt thereof, a higher fatty acid ester such ashydrogenated oil, camauba wax, beeswax, and the like. The coatingmaterial normally accounts for 1 to 80% by weight of the pharmaceuticalcomposition. According to this document the coated granules may beproduced by a conventional granulating method or by microencapsulationand it is also possible to formulate the active ingredient into thenon-coated components.

Conventionally in the art, granules are aggregates formed byagglomeration (also referred to as granulation) of powder particlesthrough the sticking together of individual feed material components.Although the said individual components may not segregate, the granulesthemselves may segregate if there is a wide size distribution. If thisoccurs in the tablet machines, products having large weight variationswill result because these machines fill by volume rather than weight.This will lead to an unacceptable distribution of the biologicallyactive ingredient content within the batch of finished product eventhough the said ingredient is evenly distributed by weight through thegranules. Therefore there is a need for solving the inherent aforesaiddisadvantages of granules.

As is well known in the art, beads (or pellets) are distinguishable fromgranules. Pelletization is an agglomeration process that converts finepowders or granules into small, free-flowing, spherical orsemi-spherical units. As opposed to the process of granulation, theproduction of beads results in a narrow size-range distribution. Themore spherical nature of beads compared to granules provides better flowand reduces segregation due to shape differences. Also, the surfacemorphology of beads is optimal for applying a functional coating.

Hence, a second approach to produce such sustained release tabletsinvolves the mixing and compaction of biologically activeingredient-loaded beads with softer inert cushioning beads which deformat lower pressures during tabletting to prevent the fracture of thecoated beads. For instance, WO 97/25029 discloses tablets containing (i)coated pellets of specific diameter and crushability comprising anactive ingredient and preferably provided with controlled releaseproperties, (ii) deformable pellets of specific diameter andcrushability comprising a plastically deformable material having amelting point of no more man 70° C. such as an ester, ether or salt of afatty acid having at least 12, preferably around 18 carbon atoms(suitably a glyceryl mono-, di- or triester of palmitic and/or stearicacid), further comprising 10 to 80% of a cellulosic derivative binderand further optionally comprising a water-insoluble inorganic powderdiluent and (iii) pellets comprising a disintegrating component,preferably a water-insoluble inorganic salt. The pellets are used in aweight ratio active pellets: deformable pellets:disintegrating pelletsin the range 1:(0.2-5.0): (0.2-5.0). In this document, the crushabilityof the deformable pellets is said to be important to achieve theprotection or cushioning of the active pellets in the tablettingprocedure. However alternatives solutions within this second approachhave often failed. For instance the production of softer inertcushioning beads containing microcrystalline cellulose was notsuccessful when water and/or alcohol was used as the granulating agent.

In order to overturn this difficulty, U.S. Pat. No. 5,780,055 disclosescushioning beads having a diameter of about 0.2 to 2.0 mm, prepared byextrusion-spheronization followed by freeze-drying and comprisingmicrocrystalline cellulose optionally admixed with a disintegrant and/ora filler. The said beads are useful for making tablets when mixed withbiologically active ingredient-loaded beads optionally coated with orcontaining a material for controlled or sustained release properties.The cushioning beads of this document are required to fragment initiallyinto progeny primary powder particles followed by plastic deformation inorder to held the tablet together by excipient-excipient contact. Thisprior art is thus limited to the use of a specific productiontechnology, therefore a need remains for a technical solution to theabove disclosed quality problems which can at the same time provide theindustrial flexibility associated with the possibility to resort tovarious production technologies.

In summary, the formulation of ready-made suspensionscontaining-controlled release beads have been associated with prematureleaching of the biologically active ingredient. The use of a dispersibletablet to form an instantaneous suspension can circumvent this problemtogether with the possibility of administering large doses ofbiologically active ingredients. The ideal tablet to form aninstantaneous sustained release suspension should disintegrate quickly(less than 5 seconds) in water followed by the formation of a viscoussuspension (within 1 to 2 minutes) to delay the settling of thebiologically active ingredient-loaded membrane-coated beads until thedose is swallowed by the patient. In order to formulate this tabletthree components are deemed to be necessary:

-   (1) biologically active ingredient-loaded membrane-coated beads    intended to deliver the dose over a long period of time;-   (2) a viscosity enhancer capable of delaying the sedimentation of    the biologically active ingredient-loaded beads; and-   (3) a filler system capable of producing mechanically strong    compacts while protecting the biologically active ingredient-loaded    beads from fracturing.

However none of the technical solutions available from the prior artprovides the capability of solving the various above-mentioned problemsat the same time. The present invention is based on the unexpectedobservation that the drawbacks of the prior art may be overcome whilenot requiring that the filler system initially fragment into progenyprimary powder particles followed by plastic deformation in order toheld the tablet together by excipient-excipient contact. The presentinvention therefore results from the selection of a cushioning beadmeeting this condition

SUMMARY OF THE INVENTION

An object of the present invention is to provide compactible cushioningbeads which may be useful for, among others, producing by compaction awide range of solid shaped articles of biologically active ingredients.Another object of the present invention is to provide water-dispersibletablets having high tensile strength. Still another object of thepresent invention is to provide tablets containing beads which give riseto sustained delivery of a biologically active ingredient.

Yet another object of the present invention is to provide tabletscontaining a swellable material able to rapidly generate viscosity whencoming in contact with water. An additional object of the presentinvention is to provide tablets which disintegrate rapidly in water, andform a homogenous suspension which can be easily swallowed by childrenand the elderly, with minimal effect on the biologically activeingredient release properties. A further object of the present inventionis to provide tablets which disintegrate rapidly in water, and form ahomogenous suspension when large doses of biologically active ingredientare needed, but where swallowing of a large tablet or capsule raises aproblem. Another object of the present invention is to provide tabletswhich can be manufactured by a wide range of production technologies.Yet another object of the present invention is to provide a method oftreatment of a mammal or a plant using ready measured doses ofbiologically active ingredient even for the administration of largedosages.

These and other objects of the present invention, which will be apparentfrom the detailed description of the invention provided hereinafter,have been met, in one embodiment, by biologically inactive cushioningbeads for making solid shaped articles containing biologically activeingredients by compression, comprising at least one compressiblecushioning component consisting essentially of a microcrystallinehydrocarbon wax or a natural wax, the said wax being at least about 30%by weight of the biologically inactive cushioning beads.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the distribution of molecular chain lengths in varioussamples of microcrystalline hydrocabon waxes used according to thepresent invention.

FIG. 2 shows the output of a gas chromatography test for amicrocrystalline hydrocarbon wax used in accordance with the presentinvention.

FIG. 3 shows the percentage of hydrocarbons of all kinds as a functionof the hydrocarbon chain length in a microcrystalline hydrocarbon waxused according to the present invention.

FIG. 4 shows the percentage of linear (normal) hydrocarbons as afunction of the hydrocarbon chain length in a microcrystallinehydrocarbon wax used according to the present invention.

FIG. 5 shows the percentage of branched (iso) hydrocarbons as a functionof the hydrocarbon chain length in a microcrystalline hydrocarbon waxused according to the present invention.

FIG. 6 shows the dissolution profile of a first formulation of tabletscomprising beads of a microcrystalline hydrocarbon wax according to thepresent invention.

FIG. 7 shows the dissolution profile of a second formulation of tabletscomprising beads of a microcrystalline hydrocarbon wax according to thepresent invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention may provide biologically inactive cushioning beadscomprising at least one compressible cushioning component consistingessentially of a microcrystalline hydrocarbon wax or a natural wax, thesaid wax being at least about 30% by weight of the biologically inactivecushioning beads and which are useful for making solid shaped articlescontaining biologically active ingredients by compression.

The present invention may also provide cushioning beads for making solidshaped articles containing biologically active ingredients bycompression, comprising at least one compressible cushioning componentcomprising a hydrocarbon wax or a natal wax, the cushioning beadsincluding at least 5% by weight of an excipient dispersed throughout thehydrocarbon or natural wax. The excipient is preferably a disintegrant.

The present invention may provide a method for treating a plant or amammal in need of a biological or therapeutic treatment by administeringto the mammal or bringing the said plant into contact with an efficientamount of a biologically active ingredient in the form of a solid shapedarticle containing biologically active ingredient-loaded beads andfurther comprising biologically inactive cushioning beads comprising atleast one compressible cushioning component comprising a hydrocarbon waxor a natural wax, the cushioning beads also including at least 5%excipient dispersed throughout the wax. The excipient is preferably adisintegrant.

The present invention may also provide a method for treating a mammal ora plant in need of a medication by administering to said mammal orcontacting the plant with an efficient amount of a biological ortherapeutic treatment with a substance containing a biologically activeingredient in the form of a solid shaped article containing biologicallyactive ingredient-loaded beads and further comprising biologicallyinactive cushioning beads comprising at least one compressiblecushioning component consisting essentially of a microcrystallinehydrocarbon wax or a natural wax, the said wax being at least about 30%by weight of the biologically inactive cushioning beads.

The term “microcrystalline hydrocarbon wax” is used herein to mean arefined synthetic wax derived from petroleum, having a dynamic viscosityat 98.9° C. (DIN 52007) greater than or equal to about 2 mPa.s andmeeting U.S.Food and Drug Administration (FDA) standards. The said waxmay, if needed, be characterized by further parameters like refractiveindex, melting point (ASTM D3945), congealing point (ASTM D 938 or DINISO 2207), penetration (ASTM D 1321 or DIN 51579), odour (ASTM D1833),ultraviolet absorption (21 CFR 172.886) and colour (ASTM D1500).According to the present invention, preference is given towater-insoluble microcrystalline hydrocarbon and natural waxes.

A microcrystalline hydrocarbon wax for use in the present invention maybe obtained from the highest boiling fraction of a crude oil, hence itsdetailed constitution depends on the source of the crude oil and thedegree of refining to which it has been subjected prior to waxseparation and refining. As is well known in the art, microcrystallinehydrocarbon waxes display physico-chemical properties quite differentfrom paraffin waxes (for instance much higher molecular weights) andhave a very delicate crystalline structure, the crystals of which may beof a fine needle or short plate type.

In the manufacture of conventional microcrystalline hydrocarbon waxes,the bottom stream from a vacuum tower or “bright stock” is deasphaltedto produce a heavy residual oil which is then extracted to partiallyremove aromatics. Hydrocarbonaceous feeds from which underwaxed brightstocks may be obtained usually contain aromatic compounds as well asnormal and branched paraffins of very high chain lengths. These feedsusually boil in the gas oil range. Typical feedstocks are vacuum gasoils with normal boiling ranges above about 350° C. and below about 600°C., and deasphalted residual oils having normal boiling ranges aboveabout 480° C. and below about 650° C. Reduced topped crude oils, shaleoils, liquefied coal, coal, coke distillates, flask or thermally crackedoils and other heavy oils can also be used as the feed source. The“microcrystalline hydrocarbon wax” as used herein may be obtained from adeoiled (i.e. containing less than about 5 weight % oil) wax having amelting point up to about 95° C. which is recovered from thisdeasphalted, extracted oil by dewaxing and deoiling. The said deoiledwax is characterised by a poor odour and a dark colour and containsaromatic impurities as shown by ultraviolet absorption tests, thus itmust be further refined in order to yield a product meeting FDAstandards (heavy metal content, ultraviolet absorption, colour, odour,and colour stability). For this purpose, it may be contacted with solidabsorbent materials such as bauxite or clay to absorb the aromaticcompounds imparting unfavourable properties to the wax. For instance,catalytic refining of the wax in the presence of hydrogen, orhydrofining, is known from U.S. Pat No. 3,052,622 disclosingsimultaneously deasphalting and extracting the aromatics via theso-called Duo-Sol process to obtain a waxy petroleum residue which isthen hydrofined by passing the wax, in the presence of hydrogen, over acatalyst of nickel oxide on bauxite. The hydrofined product is thendewaxed via a conventional solvent dewaxing process using toluene andmethylethylketone. Also U.S. Pat. No. 4,608,151 also discloses a processfor making a high molecular weight microcrystalline hydrocarbon waxcomprising:

-   -   in a first step, hydrodenitrification of a hydrocracked        underwaxed bright stock using e.g. a sulphurated nickel-tin or        nickel-molybdenum hydrotreating catalyst having a siliceous or        alumina matrix,    -   in a second step, hydrofinishing the product resulting from        first step using, e.g. an unsulphurated nickel-tin or palladium        hydrotreating catalyst having a siliceous or alumina matrix, and    -   in the third step, solvent dewaxing the product resulting from        second step while using a conventional solvent such as a mixture        of methylethylketone and toluene.

For the performance of the present invention, it is preferable to use amicrocrystalline hydrocarbon wax having a congealing point between about50° C. and 90° C. and which is water-insoluble. The microcrystallinehydrocarbon wax usually comprises a mixture of linear (normal) andbranched (iso) hydrocarbons, According to a preferred embodiment of thepresent invention, the said mixture comprises from about 30 to about 90%by weight of linear hydrocarbons and from about 10 to about 70% byweight of branched hydrocarbons. Also preferably, the microcrystallinehydrocarbon wax will be substantially free from unsaturatedhydrocarbons. According to another preferred embodiment of the presentinvention, over 98% of the molecules of the microcrystalline hydrocarbonwax have a molecular chain length (as determined by high temperaturecapillary gas chromatography) ranging from 20 to 75, most preferablyfrom 20 to 62, carbon atoms.

According to a preferred embodiment of the present invention, thedistribution of molecular chain lengths within the microcrystallinehydrocarbon wax is such that less than 6% of the molecules have lessthan 25 carbon atoms, 6 to 50% of the molecules have 25 to 29 carbonatoms, 20 to 45% of the molecules have 30 to 34 carbon atoms and 7 to70% of the molecules have at least 35 carbon atoms. More preferably, thesaid distribution is such that less than 5% of the molecules have lessthan 25 carbon atoms, 10 to 25% of the molecules have 25 to 29 carbonatoms, 30 to 45% of the molecules have 30 to 34 carbon atoms and 30 to45% of the molecules have at least 35 carbon atoms.

As a substitute to the microcrystalline hydrocarbon wax obtained throughrefining or hydrofinishing of a deoiled petroleum wax as disclosedabove, a synthetic petroleum wax of similar characteristics (dynamicviscosity, refractive index, distribution of molecular weights,crystalline structure and the like) may also be used within the scope ofthe present invention, which is the product of catalytic polymerizationof ethylene or copolymerization of ethylene with minor amounts of linearalpha-olefins having from 3 to 12 carbon atoms (e.g. propylene,1-butene, 1-hexene, 1-octene) or maleic anhydride. According to thepresent invention, such a synthetic petroleum wax is designed to meetthe FDA standards and preferably has a number average molecular weightfrom about 500 to about 1,200. Here again, preference is given to awater-insoluble wax.

As a substitute to the above disclosed embodiments of microcrystallinehydrocarbon waxes, there may also be used natural waxes, preferablytheir grades meeting FDA standards, or mixtures of such natural waxes,showing essentially similar physico-chemical characteristics (dynamicviscosity, refractive index, distribution of molecular weights, meltingpoint, congealing point, proportions of linear and branchedhydrocarbons, and the like), crystalline structure (as determined bythose skilled in the art) and behaviour (cushioning effect) whensubjected to compression. Examples of natural waxes include vegetablewaxes and insect waxes such as, without limitation:

-   -   canauba wax, a yellowish-white sticky exsudation on the leaves,        berries and stalks of Copernicia cerifera, a palm tree found in        South America, and especially Brazil. Having a melting point of        84° C., it is available from Pontes Industria de Cera Ltda        (Fortaleza, Brazil). It is believed to consist largely of        myricyl cerotate (a 56 carbon atoms ester) and myricyl alcohol        (30 carbon atoms),    -   candelilla wax, an exsudate on the leaves and stems of Euphorbia        antisyphilitica, a plant growing in the Chihuahuan desert of        northeastern Mexico and southwestern United States. Having a        melting point of 71° C., it is available from Multiceras S.A.        (Mexico) under the tradename REAL™. Being opaque to translucent,        it is extracted by boiling the leaves with water and sulfuric        acid in a tank, then skimming off the crude wax (called cerote)        floating on the top of the tank, then cooling the cerote and        breaking it into smaller pieces before re-heating and removing        impurities by passing the liquid wax through a filter press,    -   palm wax, formed on the trunk of Ceroxylan andicola in tropical        America,    -   lignite wax, having a melting point of 80° C., obtained by        exhausting the distillation products of lignite by means of        benzene. It is believed to contain montanic acid (29 carbon        atoms) together with ceryl montanate (56 carbon atoms) and        myricyl montanate (60 carbon atoms),    -   ozokerite, a waxy mixture of hydrocarbons occuring in        association with petroleum with often unpleasant odor,    -   ceresin wax, usually defined as a purified form of ozokerite        consisting of a mixture of hydrocarbons, namely        iso-hydrocarbons, of average molecular weight somewhat higher        than that of paraffin wax,    -   lardaceine, a wax formed on the shell of Ceroplastens rubens, an        insect living on the tea plant, and containing a substantial        amount of ceromelissic acid having a melting point of 94° C.,        and    -   China wax, secreted by the Chinese ash-tree as a result of sting        by Coccus Ceriferus and mainly containing ceryl cerotate.

As a substitute to the above embodiments of the present invention mayalso be us d compounds selected from saturated hydrocarbons having from25 to 31 carbon atoms, saturated alcohols having from 25 to 31 carbonatoms, saturated monocarboxylic acids having from 25 to 31 carbon atoms,esters obtained from the said alcohols and monocarboxylic acids (thushaving from 50 to 62 carbon atoms), including for instance:

-   -   neocerylic (neocerotic) alcohol (25 carbon atoms),    -   neocerotic (pentacosanoic) acid (25 carbon atoms),    -   ceryl cerotate (52 carbon atoms),    -   montanic (nonacosanoic) acid (29 carbon atoms),    -   myricic alcohol or hentriacontanol (31 carbon atoms),    -   cerylic (cerotic) alcohol or heptacosanol (27 carbon atoms),    -   cerylic (hexacosanoic) acid (26 carbon atoms),    -   myricyl cerotate (56 carbon atoms).        as well as their mixtures in proportions providing        characteristics (dynamic viscosity, refractive index,        distribution of molecular weights, melting point, congealing        point, proportions of linear and branched hydrocarbons,        crystalline structure and the like) similar to those of the        synthetic and natural waxes described hereinbefore.

In addition to the microcrystalline hydrocarbon wax or natural wax ofsubstantially Similar characteristics, the cushioning beads of thepresent invention may include up to about 70% by weight of anothercompressible biologically inactive cushioning component or at least abiologically inactive but pharmaceutically acceptable additive(excipient) such as colorant, sweetener (e.g. sucrose, mannitolsaccharin and aspartame), flavoring agent (e.g. vanillin), bufferingagent, filler, disintegrating agent and/or swellable material.Preferably the cushioning beads of the present invention include atleast about 5% by weight of at least one such biologically inactivepharmaceutically acceptable additive (excipient) distributed throughoutthe beads, for instance in the form of an intimate mixture of wax andexcipient. A disintegrating agent is especially useful as an excipientfor providing quick-disintegrating characteristics when making a solidshaped article containing biologically active ingredients bycompression.

Swellable materials (also called viscosity enhancers) are substanceswhich form colloidal dispersions in an aqueous environment, thecolloidal particles forming a three-dimensional network or grid-likestructure throughout dispersion may become less viscous or dissolve inresponse to pH changes or enzymes degradation, in such a way thatdiffusion through the gel does not influence the release of activesubstance from the particles. The particular swellable material used isnot critical to the present invention : examples of useful swellingagents include hydrophilic polymers, such as sugars (dextrose, glucoseand sucrose), certain cellulose derivatives such as such as sodium orcalcium carboxymethylcellulose, hydroxypropyl cellulose orhydroxypropylmethyl cellulose, pregeletanized starches, polysaccharides,pectin agar, carrageenan, clays, hydrophilic gums like acacia gum, guargum, arabic gum and xanthan gum, alginic acid, algmates, dextran,pectins (available under the tradenames Visquick® and InstaThick® fromZumbro Inc., Hayfield, Minn.) and carbomer resins.

Carbomer resins (available under the tradenames Carbopol® 934P, 971P and974P pharmaceutical grades from B.F.Goodrich Cleveland, OH.) arecrosslinked acrylic acid polymers wherein a high percentage ofcarboxylic acid groups allow the resins to be water-swellable. In thepresolvated dry state, a carbomer is tightly coiled. When dispersed inwater, carbomer begins to hydrate and uncoil, resulting in partialincrease of viscosity. It must completely uncoil to achieve the highestand most consistent viscosity, for instance by neutralization by meansof a water-soluble base such as ammonia. Neutralization results inionizing the carbomer and generating negative charges along the polymerbackbone. Repulsion of these negative charges causes expansion of themolecule, thereby causing the molecule to rapidly thicken.Overneutralization by strong bases can collapse the resin structure,resulting in a permanent loss of viscosity. Carbomers vary by molecularweight, degree of crosslinking and molecular architecture. Thesedifferences are responsible for the specific rheological characteristicsand thickening efficiency of each carbomer resin. Neutralized carbomersavailable under the tradenames Carbopol® EX161 and EX214 fromB.F.Goodrich are salts which do not require the addition of a base foruse in sustained-release oral suspensions. In solid dosage formulation,Carbopol 934 has also been used as dry tablet binder and as controlledrelease agent via a hydrophilic matrix mechanism. Carbomer resins notonly thicken solutions, but also provide a wide range of flowproperties. Like numerous polysaccharide thickeners, such as modifiedcellulosics and natural gums, carbomer resins are shear thinning(viscosity decreases with increasing shear rate). However, unlike mostlinear polysaccharides, carbomer resins display plastic rheologicalprofiles. Carbomer solutions will not flow until a minimum force, calledthe yield value is reached. Carbomer reins provide excellent stabilityto oil-in-water (otw) emulsions and suspensions. When used inconjunction with appropriate emulsifying agents and coemulsifiers,carbomer resins provide long term stability at ambient and elevatedtemperatures, as well as under freeze-thaw conditions. The yield valuecreated by carbomer resins prevents “creaming” or separation of o/wemulsions by suspending and separating the oil droplets. It also allowsparticles to be permanently suspended throughout the medium, creatingstable non-settling products, even when used at very low concentrations.One major difficulty encountered with carbomer, is its poordispersibility: the dry powder resins are highly hygroscopic and hydraterapidly when added to water or polar solvents. Thus carbomer resins willclump or incompletely hydrate when haphazardly introduced into waterbecause the surfaces of the wet agglomerates quickly solvate and form alayer which prevent rapid wetting of the dry interior. This, togetherwith the fluffy nature of carbomer, results in dispersion defects, suchas grainy texture, reduced viscosity or the presence of partially wetagglomerates. Therefore, to avoid lengthy mixing times and to preparehigh quality, reproducible carbomer resin dispersions, either properdispersion techniques should be used or carbomer should be formulated ina readily dispersible less fluffy form, such as granules or spheres, orpowder-layered on the surface of carrier seeds. In powder-layering, thebiologically active ingredient does not come in contact with the bindersolution until it is sprayed onto the inert seed material, as the binderand biologically active ingredient are sprayed from different ports. Asthe amount of binder solution needed is much less when compared to otherlayering techniques, drying will be very fast and the total process ismuch faster.

The particular disintegrating agent which may be used in the cushioningbeads is not critical to the present invention. It includes not onlywater-insoluble inorganic salts such as baryum sulfate, calcium andmagnesium carbonates (creating carbon dioxide in situ in effervescenttablets), calcium phosphate, iron oxide, magnesium oxide, dicalciumhydrogenophosphate and their mixtures but also pregelatinized ormodified stashes such as sodium starch glycolate (available under thetradenames Primojel® and Explotab®), crosslinked polyvinylpyrrolidone(available under the tradename Polyplasdone XL® from ISP Technologies,Wayne, N.J.), magnesium aluminum silicate (available under the tradenameVeegum®), sodium carboxymethylcellulose (available under the tradenameNymcel®) and other cellulose materials (such as available under thetradename Avicel® from FMC Corp., Philadelphia, PA.), cation exchangeresins (such as the potassium salt of a crosslinked carboxylic acidresin available under the tradename Amberlite ® IRP), modified cellulosegums such as croscarmellose sodium (available under the tradenamesAc-di-sol® from FMC Corp., Philadelphia, PA.) and the like. The amountof disintegrant used is also not critical to the present invention anddepends, in a manner well known in the art, upon the desired granulardensity (usually in the range of 0.5 to 1.5 mg/ml), porosity andcompactibility (usually which upon compaction provides a friability ofno more than 1%).

Fillers which may be used in the cushioning beads are not critical tothe present invention. They include for instance binding agents such asstarch, gelatin, glucose, alginic acid, sodium and calcium alginates,water-soluble acrylic polymer, polyvinylpyrrolidone, ethylcellulose,hydroxypropylmethylcellulose and the like, glidants such as fumed(colloidal) silica (such as available under the tradename Aerosil),lubricants such as magnesium stearate, talc, sodium and magnesium:lauryl sulfates, water-insoluble diluents such as dicalcium phosphateand water-soluble diluents such as lactose, sorbitol and the like.

The cushioning beads of the present invention preferably have an averageparticle size of about 0.5 to about 2.0 mm and most preferably from 0.75to 1.25 mm. They can be produced by a number of different techniquessuch as high-shear mixing, extrusion, extrusion-spheronization or byother means, as long as the said technique results in free-flowingbeads, not granules, having a narrow size distribution range. Thepreferred production process involves high-shear mixing of themicrocrystalline hydrocarbon wax or natural wax of similarcharacteristics and the optional additives (excipients) in view toachieve the average particle size mentioned above. As used herein, theterm “high-shear mixing” means mixing the beads components at a highshear rate as is readily known to those skilled in the art. Whenhigh-shear mixing is used as the production technique, the temperatureof mixing and should preferably be in the range of about 45 to about 60°C., most preferably in the range of about 50 to about 55° C.

Another production process involves fusing the microcrystallinehydrocarbon wax or natural wax of similar characteristics and theoptional additives (excipients), for instance by hot stage extrusion,and next feeding the fused mass onto a spheronizer. According to anotherembodiment of the present invention, extrusion-spheronization may becarried out by a method comprising the steps of:

-   (a) granulating the microcrystalline hydrocarbon wax or natural wax    of similar characteristics and the optional additives in the    presence of a granulating fluid, and-   (b) extruding the granulate obtained in step (a) onto a spheronizer.    Spheronization was first disclosed in U.S. Pat. No. 3,277,520 and    equipment design change has been minimal since then. The spheronizer    consists basically of a grooved horizontal plate rotating at high    speed-within a stationary vertical cylinder fitted with a door to    allow release of the pellets. Although extrusion is usually regarded    as a continuous process, spherorization equipment design limits the    extrusion-spheronization process to a batch process or multiple    batch process. The granulating fluid may be water or an aqueous    solution containing a lower alcohol, such as ethanol or propanol.    The amount of granulating fluid used affects the mechanical    properties (porosity, density, friability and compactibility) of the    beads produced. The amount of granulating fluid used depends on the    composition of the powder mixture used in step (a) and is generally    such as to provide a final solids concentration, of about 20 to 80%    by weight. The granulating fluid content and composition of the    powdery mixture granulated in step (a) must be carefully selected in    order that a suitable plastic deformability (extrudability) is    obtained. The particle size distribution of the beads obtained is    also primarily determined by the extrudate density and granulating    fluid content.

In view of their properties, the cushioning beads such as disclosedabove are useful for, among others, producing by compaction a wide rangeof solid shaped articles of biologically or therapeutically activeingredients. Thus a second object of the present invention consists of asolid shaped article containing biologically active ingredient-loadedbeads and further comprising biologically inactive cushioning beadscomprising at least one compressible cushioning component consistingessentially of a microcrystalline hydrocarbon wax or a natural wax, thesaid wax being at least about 30% by weight of the biologically inactivecushioning beads.

The term “solid shaped article” as used herein means any article beingin a hard solid state at temperatures not exceeding about 60° C. andhaving a definite geometrical shape, such as for instance ordinarytablets, effervescent tablets, multilayer tablets, sustained-releasetablets, pills, lozenges and other compressed dosage forms.

The term “biologically active ingredient” as used herein includes anypharmacologically (as well as veterinary) active substance, for instanceany drug, medication, dietary supplement or vitamin which may beadministered in the form of solid shaped articles such as definedhereinabove and especially any such active substance for whichcontrolled or sustained release is required or recommended. This enablesrelease of the active substance in the duodenum, ileum or colon ratherthan the stomach or to ensure that the active substance is released at acontrolled rate the stomach to decrease the chance of damage to thegastric mucosa. The term “biologically active ingredient” as used hereinalso includes other substances such as chemicals having biologicalactivity in nature such as fertilizer, pesticides, herbicides,disinfectants and the like, for which slow release may be advantageousand that are required per se in unit form for adding to a predeterminedamount of water, solvent or mixtures of solvents to produce a solutionof precisely controlled concentration and efficiency. Examples of thelatter substances are trace additives for maintaining the safety ofwater supplies, nutritional and trace additives for fish ponds, anddisinfecting agents for swimming pools. Examples of drugs andmedications within the scope of the present invention include, withoutlimitation, microencapsulated potassium chloride, lithium salts,acetylsalicylic acid (aspirin), diclofenac sodium, aceclofenac,indomethacin, nonsteroidal anti-inflammatory drugs, calcium salts,antiosteoporotics, muscle relaxants, abortives, alcohol deterrents,anabolics, analgesics, androgens, anorexics, antiamebics,antiarrhythmics, antiarthritics, antibacterials, anticholinergics,anticoagulants, anticonvulsants, antidepressants, antidiabetics,antidiarrheals, antidiuretics, antiemetics, antihistaminics,antihyperlipoproteinemics, antihypertensives, antihyperthyroids,antihypotensives, antimigraine, antiparkinsonians, antipsychotics,antispasmodics, antithrombotics, antiulceratives, antivirals,anxiolytics, bronchodilators, antitussives, antipyretics, calciumregulators, cardiotonics, choleretics, cholinergics, stimulants of thecentral nervous system, contraceptives, decongestants, diuretics,emetics, estrogens, glucocorticoids, hematinics, hemostatics,immunomodulators, mucolytics, nootropics, progestogens, respiratorystimulants, cerebral, coronary and peripheral vasodilators,vasoprotectants, vitamins, antibiotics and the like.

The particular pesticide used is not critical to the present invention.Examples of such pesticides include clomazone, sulfentrazone,trifluralin and mixtures thereof. The particular herbicide used is notcritical to the present invention. Examples of such herbicides includezeta-cypermephrin, cadusafos and bifenthrin. The particular fertilizerused is not critical to the present invention. Examples of suchfertilizers include natural phosphates and synthetic superphosphates.

The solid shaped article of the present invention preferably containsthe biologically active ingredient in the form of beads having adiameter substantially similar to the diameter of the cushioningwax-containing beads, i.e. a diameter preferably ranging from about 0.5to about 2.0 mm and most preferably from 0.8 to 1.2 mm.

The means for preparing the biologically active ingredient-loaded beadsis not critical to the present invention. For example, the biologicallyactive ingredient-loaded beads can be prepared by techniques well-knownin the art such as extrusion-spheronization, solution/suspensionlayering, powder layering, balling (a pelletization process in whichfinely divided particles are converted, upon the addition of appropriatequantities of liquid, to spherical particles by continuous rolling ortumbling action) or fluidized bed roto-granulation, as long as the saidtechnique results in free-flowing beads, not granules, having a narrowsize distribution range.

Optionally, a coating material may be applied, preferably by means ofthe film-coating process, to the biologically active ingredient-loadedbeads for controlling or sustaining the release properties of thebiologically active ingredient or for taste masking or for impartingresistance to gastric fluid. Film coating of a tablet involves thedeposition, usually by spraying, of a thin film of polymer surroundingthe tablet core. The coating solution contains a polymer in a suitableliquid solvent and optionally mixed together with other ingredients suchas plasticizers, pigments and/or colorants. After spraying, the dryingconditions permit to remove substantially all of the solvent

The particular coating material used is not critical to the presentinvention, and depends upon the purpose of the coating material, e.g.desired release profile, ability to stay intact and/or to withstand themechanical stress of compaction without cracking. However, as is readilyunderstandable from the purpose of the present invention, the solidshaped articles of the invention are most useful when the said coatingmaterial is brittle. The term “brittle” is used herein to denote acoating that would crack if the solid shaped article is tableted orformed by compression in the absence of the cushioning beads of thepresent invention. Examples of coating polymers useful for controllingor sustaining the release properties of the biologically activeingredient and/or taste masking include derivates of cellulose such asmethylcellulose, hydroxypropylmethylcellulose and ethylcellulose, suchas those marketed under the tradenames Surelease® and Aquacoate®,polyvinylpyrrolidone and aminoalkyl methylacrylate copolymers. Examplesof coating polymers useful for imparting resistance to gastric fluidinclude shellac, cellulose acetate phthalate (Aquateric®), celluloseacetate trimelliate, hydroxypropylmethylcellulose phthalate, polyvinylacetate phthalate (Coateric®), hydroxypropyl methylcellulose acetatesuccinate, carboxymethylethylcellulose, styrene/acrylic acid copolymers,methacrylic acid copolymers, maleic anhydride copolymers and the like.Examples of plasticizers which may be mixed together with the coatingpolymer include, without limitation, polyethyleneglycol, glycerol,phthalate esters, triethylcitrate, etc.

The thickness of the coating layer used is not critical to the presentinvention. It depends upon the desired release profile of thebiologically active ingredient and typically is in the nanometer tomicron ranges. Alternatively, the above-listed polymers and optionallyplasticizers can be incorporated into a matrix system together with thebiologically active ingredient-loaded beads to sustain its action, e.g.during dry powder mixing prior to granulation, or in the granulationsolution prior to extrusion-spheronization, or within the othertechniques conventionally used to produce pellets or beads. In such acase, the amount of polymers and optionally plasticizers is not criticalto the present invention, and depends upon the purpose of the materiale.g. the desired release profile of the biologically active ingredient.

The weight ratio of cushioning beads to biologically activeingredient-loaded beads is not critical to the present invention and ispreferably between about 30:70 and 70:30, most preferably between about40:60 and 60:40.

The solid shaped articles of the present invention may also contain aswellable material (also called viscosity enhancer) which may be presenteither as individual beads or may be a component of the biologicallyactive ingredient loaded-beads, if these beads are intended forimmediate delivery of the biologically active ingredient, i.e. where nosustained action or coating polymer is used. In the latter case, theamount of viscosity enhancer is not critical to the present invention.Viscosity enhancer beads may be produced by extrusion-spheronizationusing a water-alcohol solution as the granulating fluid, or bypowder-layering. This avoids the detrimental effects of ionic salts orpH modifiers on the ability of the viscosity enhancer to increaseviscosity when hydrated. Also, extrusion-spheronization of the viscosityenhancer using a hydroalcoholic granulating fluid reduces the tackinessthereof. The particular water-alcohol solution used is not critical tothe present invention and may include ethanol, propanol or a mixturethereof.

When viscosity enhancer beads are present in the solid shaped articlesof the present invention, their weight ratio to cushioning beads and/orbiologically active ingredient loaded-beads is not critical to thepresent invention, and depends upon the desired viscosity required tokeep the biologically active ingredient-loaded beads suspended until thesuspension is swallowed by the patient. Typically, the viscosityenhancer, either as individual beads or as a component of thebiologically active ingredient-loaded beads, should be present in anamount to achieve an apparent viscosity at 20° C. of 30 to 3,000 mPa.s,preferably 500 to 1000 mPa.s.

The solid shaped articles of the present invention may also containcomponents traditionally used in the formulation of such articles, e.g.,favoring agents, lubricants, sweeteners, colorants and/or bufferingagents, such as those listed above.

The solid shaped articles of the present invention are manufactured bycompression or compaction of biologically active ingredient-loadedbeads, optionally coated by means of a polymer, and cushioning beadscomprising a microcrystalline hydrocarbon wax or a natural wax ofsubstantially similar characteristics. Such a production technique iswell known in the art and usually referred as tablet production ortableting. The ingredients in the form of beads (or pellets) are fedinto a die, then compressed between punches, and finally the compactedmass is ejected from the die.

This requires that:

-   -   the beads must be sufficiently free-flowing to uniformly flow        into the relatively small volume of the die in a very short        time,    -   the beads, when subjected to a force from the punches, cohere to        form a compact of adequate strength, and    -   adhesion of the tablet to the punches and dies must be avoided,        otherwise damage to both tablet and press will follow when        removing the tablet from the die. This can be suitably achieved        by compacting a mixture of biologically active ingredient-loaded        beads, cushioning beads according to the present invention, and        at least a lubricant. The particular lubricant is not critical        to the invention and includes, among others, hydrogenated oils.

Detailed operation of tablet presses include embodiments well known inthe art such as wet massing, fluidized bed granulation, spray drying,precompression and direct compression, which are all applicable to thepresent invention.

Tableting of the beads is effected according to the type and ratio ofthe cushioning beads, biologically active ingredient-loaded beads, andoptionally viscosity enhancer beads and other components present in thesolid shaped articles of the present invention, as well as the type ofcoating material, if any, used for the biologically activeingredient-loaded beads. The compression or compaction pressure used inthe production of the solid shaped articles is not critical to thepresent invention and depends upon the above-mentioned parameters and isusually about 5 to 200 MPa, preferably about 10 to 150 MPa.

The present invention also provides a method of biologically treating amammal or a plant by using solid shaped articles such as describedhereinbefore. In particular, the present invention provides a method fortreating a mammal in need of a medication by administering to saidmammal an efficient amount of said medication containing a biologicallyactive ingredient in the form of a solid shaped article containing thesaid active ingredient and further comprising cushioning beadscomprising a microcrystalline hydrocarbon wax or a natural wax ofsubstantially similar characteristics. The biologically activeingredient may be, in the case of a human, any pharmaceuticallyefficient compound such as specified above or, in the case of an animalany veterinary substance.

The present invention further provides a method for treating a plant inneed of a biological treatment by bringing the said plant into contactwith an efficient amount of a biologically active ingredient in the formof a solid shaped article containing the said active ingredient andfurther comprising cushioning beads comprising a microcrystallinehydrocarbon wax or a natural wax of substantially similarcharacteristics. If needed, treatment of the plant according to thepresent invention may be followed by watering the plant in order tofacilitate release of the active ingredient.

As is readily apparent, the solid shaped articles of the presentinvention provide numerous advantages over the prior art when used forthe biological treatment of mammals and plants such as mentioned in theabove methods of treatment. They are able to provide a formulation whichdisintegrates rapidly in water to form an instantaneous homogenoussuspension of adequate viscosity to be swallowed without prematurerelease from controlled-release particles while providing a readymeasured dose, even for the administration of large dosages. When usinga viscosity enhancer, the solid shaped article of the present inventionare useful for preparing an immediate release suspension (when nocoating polymer is provided on the biologically active ingredient-loadedbeads or when no polymer is incorporated into the matrix system of thebiologically active ingredient-loaded beads) or a sustained releasesuspension (when such a polymer is coated onto or incorporated into thebiologically active ingredient-loaded beads), and rapid disintegrationoccurs when the solid shaped article of the present invention isimmersed in water or an aqueous solution. Disintegration occurs within acouple of seconds and give rise to the in situ formation of a suspensionover a period of less than 1 minute. The in situ suspension is usefulfor preparing sustained release liquid products namely for youngchildren and elderly patients who cannot swallow tablets or capsules, orfor patients who require large doses of biologically active ingredients,where swallowing large dosage forms is difficult

The following examples are provided for illustrative purposes only andare in no way intended to limit the scope of the present invention

In the examples below, all percentages are weight percentages, unlessotherwise indicated.

EXAMPLE 1 Specifications of Microcrystalline Hydrocarbon Wax Suitablefor Making Cushioning Beads

A refined pharmaceutical grade of microcrystalline hydrocarbon waxmeeting the requirements for making cushioning beads is commerciallyavailable from Paramelt N.V. (Heerhugowaard, Netherlands). Its mainphysical characteristics are as follows:

-   -   congealing point (DIN ISO 2207): 58-62° C.    -   penetration (DIN 51579): 10-14 1/10 mm    -   melting point (ASTM D 3945): 59-63° C.    -   refractive index: 1.422-1.426    -   dynamic viscosity at 98.9° C. (DIN 52007-2): 3-4.5 mPa.s

A representative sample of this microcrystalline hydrocarbon wax wasanalyzed by gas chromatography, resulting in the chromatograph outputgiven in FIG. 2. This includes a series of well spaced peaks, thedistance between two peaks being related to a difference by one atom inthe hydrocarbon chain length. The distribution of carbon chain lengthsin FIG. 2 shows a nearly symmetrical form around a peak of 28-29 carbonatoms, with a high molecular weight tail above a chain length of 40carbon atoms. FIG. 2 shows that over 98% of the compounds of this samplehave a chain length from 20 to 55 carbon atoms. In more details, theconstitution of this microcrystalline hydrocarbon wax according tocarbon chain length is as follows:

-   Chain length group No.1 (from C20 to C24): 5.31%-   Chain length group No.2 (from C25 to C29): 48.71%-   Chain length group No.3 (from C30 to C34): 38.36%-   Chain length group No.4 (from C35 to C39): 6.63%-   Chain length group No.5 (from C40 to C44): 0.89%-   Chain length group No.6 (from C45 to C49): 0.10%

FIG. 1 is a graph representing the above percentages per chain lengthgroup for this sample and for sample A (see example 6 hereafter) ofanother microcrystalline hydrocarbon wax from the same supplier ParameltN.V.

EXAMPLE 2 Manufacturing of Cushioning Beads Comprising MicrocrystallineHydrocarbon Wax

Blending of a mixture comprising:

-   Microcrystalline hydrocarbon wax of example 1 12.5 kg-   Drum duid corn starch (Cerestar, Vilvoorde, Belgium) 8.35 kg-   sodium starch glycolate Explotab® (Barentz, Zaventem,-   Belgium) as a disintegrating agent: 4.15 kg    is performed in a high shear mixer (Vactron 75, GEI Collette,    Wommelgem, Belgium). The different ingredients are mixed in the    mixing bowl and next head. The temperate of the jacketed bowl is set    at 70° C. and the powder mixture is homogenised during 35 minutes,    after which time the mixture is becoming plastic and the temperature    of the mixture is 58° C. During heating and homogenisation of the    powder, the mixing arm is set at 100 rpm. Next the cooling phase is    started by adding 1 kg CO₂ pellets and the mixing and chopper arms    are set at 200 rpm. Some more C₂ pellets are added up to a total    amount of 25 kg. After 15 minutes mixing time, the temperate reaches    50.5° C. The energy transfer from the mixing and chopper arms allows    a temperature increase up to 52.5° C. and this temperature is kept    by adding another 0.5 kg of C₀₂ pellets. After a pelletization    period of 7 minutes the bowl is opened and the pellet mass is taken    from the bowl and sieved using the appropriate sieves, yielding    particle sizes ranging from 0.75 to 125 mm and an average size of 1    mm.

EXAMPLE 3 Production of Tablets Comprising Microcrystalline HydrocarbonWax Cushioning Beads

Round flat tablets (13 mm) containing diltiazem a calcium channelblocker with coronary vasodilating activity falling in the therapeuticcategories of antianginals, antihypertensives and antiarrhythmics, asthe biologically active ingredient are produced using the followingcomposition:

-   -   Diltiazem coated pellets 57.90%    -   Cushioning beads of example 2 38.6%    -   Explotab® 2.5%    -   Lubritab® 1.0%

The above mixture is first homogeinized during 10 minutes and thencompacted by means of an excentric tabletting machine while filling thematrix hole with 800 mg of the said mixture, thus achieving an initialcompaction pressure of 500 kg. Thanks to the use of Lubritab®, ahydrogenated oil, as a lubricant in the above formulation, it waspossible to prevent adhesion of the resulting tablet to the compactingmachine and consequently to avoid damage to the tablet during itsejection from the said machine. Similar tablets may be obtained whileusing compaction pressures of 1,000 and 1,500 kg respectively.

EXAMPLE 4 Production of Tablets Comprising Microcrystalline HydrocarbonWas Cushioning Beads

Round flat tablets (13 mm) containing diltiazem as the biologicallyactive ingredient are produced by the same process as in example 3 withcompaction pressures of 500 kg and 1,000 kg respectively, using thefollowing composition:

-   -   Diltiazem coated pellets 58.14%    -   Cushioning beads of example 2 38.76%    -   Ac-di-Sol® 2.00%    -   Lubritab® 1.00%    -   Aerosil ® (fumed silica) 0.10%

EXAMPLE 5 In vitro Dissolution Profile of Tablets ComprisingMicrocrystalline Hydrocarbon Wax Cushioning Beads

The dissolution profiles of the tablets produced in example 3 weredetermined while using a dissolution testing apparatus VK 8000 (VankelIndustries Inc., New Jersey) and using the following dissolutionparameters:

-   -   dissolution medium: distilled water    -   volume of dissolution medium: 900 ml    -   rotating speed: 0 rpm    -   temperature: 37.5° C.    -   sampling times: 0.5, 1, 2, 4, 8 , 12 and 16 hours    -   same volume: 5 ml    -   concentration determination method: spectrophotometry at 240        (Perkin-Elmer, Lamda 12).

The results of such determinations are represented in FIG. 6 showingdissolution percentages as a function of time for tablets compressed atpressures of 500 kg, 1,000 kg and 1,500 kg respectively. These resultsshow that the dissolution profile improves when the compaction pressureincreases up to 1,000 kg and then decreases when the compaction pressurefurther increases up to 1,500 kg. Anyhow, a dissolution percentage of atleast 80% is readily achievable within 8 hours when properly selectingthe compaction pressure.

EXAMPLE 6 In vitro Dissolution Profile of Tablets ComprisingMicrocrystalline Hydrocarbon Wax Cushioning Beads

The dissolution profiles of the tablets produced in example 4 weredetermined according to the same method as in example 5. The results ofsuch determinations are represented in FIG. 7 showing dissolutionpercentages as a function of time for tablets compressed at pressures of500 kg and 1,000 kg respectively. These results show a betterdissolution profile for a compaction pressure of 500 kg. Again, adissolution percentage of 80% is readily achievable within 8 hours byproperly selecting the compaction pressure. FIG. 7 also provides thedissolution profile of a non-compacted diltiazem pellets for purpose ofcomparison.

EXAMPLE 7 Specifications of Other Microcrystalline Hydrocarbon WaxesSuitable For Making Cushioning Beads

Other products suitable for making cushioning beads are pharmaceuticalgrades of microcrystalline hydrocarbon waxes available from ParameltN.V. (Netherlands), for which gas chromatography analysis ofrepresentative samples A and B provides the distribution of hydrocarbonchain lengths as indicated in the table below.

Carbon chain length range sample A sample B C20-24 - group 1 1.65 3.73C25-29 - group 2 6.37 16.97 C30-34 - group 3 23.36 36.85 C35-39 - group4 42.52 18.74 C40-44 - group 5 19.84 7.52 C45-49 - group 6 5.82 3.92 >=C50 - group 7 0.44 12.17

A more detailed analysis of sample B has been made using hightemperature capillary gas chromatography in order to discriminate andquantify the normal (linear) forms from the branched (iso-) forms of thehomologous series of hydrocarbons which make up this microcrystallinewax. The percentages of hydrocarbon as a function of the hydrocarbonchain length are shown in FIGS. 3 to 5 where:

-   -   FIG. 3 relates to hydrocarbons of all kinds (linear and        branched),    -   FIG. 4 relates to linear (normal) hydrocarbons, and    -   FIG. 5 relates to branched (iso) hydrocarbons.

It is remarkable that the distribution of iso-hydrocarbons shows a peak(most common chain length) at 34 carbon atoms which is significantlyhigher than the peak for the distribution of linear hydrocarbons (30carbon atoms). The average number of carbon atoms is 29 for thedistribution of linear hydrocarbons, 39 for the distribution ofiso-hydrocarbons and 33 for the distribution of all hydrocarbons.Calculations from FIGS. 3 to 5 indicate that the normal toiso-hydrocarbon ratio is about 60 to 40 in this sample.

1. In a solid shaped compressed article, said solid shaped compressedarticle containing a biologically active ingredient and a hydrocarbonwax or natural wax, the improvement wherein: said solid shapedcompressed article contains the biologically active ingredient in theform of biologically active ingredient-loaded beads with a brittlecoating, said solid shaped article further comprises biologicallyinactive cushioning beads of a size of about 0.5 to 2 mm for protectingsaid brittle coating during compression or compaction, wherein saidbiologically inactive cushioning beads comprise at least onecompressible cushioning component consisting essentially of amicrocrystalline hydrocarbon wax or a natural wax, the said wax being atleast 30% by weight of the biologically inactive cushioning beads, andoptionally up to 70% by weight of another biologically inactivecompressible cushioning component or pharmaceutically acceptableexcipient, and wherein the weight ratio of the biologically inactivecushioning beads to the coated biologically active ingredient-loadedbeads is between 30:70 and 70:30.
 2. A solid shaped article according toclaim 1, wherein the biologically active ingredient-loaded beads arecoated with a coating material for controlling or sustaining the releaseproperties of the biologically active ingredient or for taste masking orfor imparting resistance to gastric fluid.
 3. A solid shaped articleaccording to claim 1, wherein the cushioning beads include at least 5%by weight of at least a biologically inactive pharmaceuticallyacceptable excipient.
 4. A solid shaped article according to claim 1,wherein over 98% of the molecules of the microcrystalline hydrocarbonwax or natural wax have a molecular chain length ranging from 20 to 75carbon atoms.
 5. A method for treating a plant in need of a biologicaltreatment or a mammal in need of a medication by bringing the said plantinto contact with an efficient amount of a biologically activeingredient or by administering to said mammal an efficient amount ofsaid medication containing a biologically active ingredient, wherein thesaid biologically active ingredient is in the form of a compressed solidshaped article containing biologically active ingredient-loaded beadscoated with a brittle coating, and further comprising biologicallyinactive cushioning beads of a size of about 0.5 to 2 mm protecting saidbrittle coating during compression, wherein said biologically inactivecushioning beads comprise at least one compressible cushioning componentconsisting essentially of a microcrystalline hydrocarbon wax or anatural wax, the said wax being at least 30% by weight of thebiologically inactive cushioning beads, and optionally up to 70% byweight of another biologically inactive compressible cushioningcomponent or pharmaceutically acceptable excipient, and wherein theweight ratio of the biologically inactive cushioning beads to the coatedbiologically active ingredient-loaded beads is between 30:70 and 70:30.6. A method according to claim 5, wherein the cushioning beads includeat least 5% by weight of at least a biologically inactivepharmaceutically acceptable excipient.
 7. A solid shaped articleaccording to claim 1, wherein the microcrystalline hydrocarbon wax ornatural wax has a dynamic viscosity at 98.9° C. (DIN 52007) greater thanor equal to 2 mPa.s and/or a congealing point between 50° C. and 90° C.8. A solid shaped article according to claim 1, wherein themicrocrystalline hydrocarbon wax or natural wax comprises a mixture of30 to 90% by weight of linear hydrocarbons and 10 to 70% by weight ofbranched hydrocarbons.
 9. A solid shaped article according to claim 1,wherein the distribution of molecular chain lengths within themicrocrystalline hydrocarbon wax or natural wax is such that less than6% of the molecules have less than 25 carbon atoms, 6 to 50% of themolecules have 25 to 29 carbon atoms, 20 to 45% of the molecules have 30to 34 carbon atoms and 7 to 70% of the molecules have at least 35 carbonatoms.
 10. A solid shaped article according to claim 1, wherein themicrocrystalline hydrocarbon wax is a product of catalyticpolymerization of ethylene or copolymerization of ethylene with minoramounts of linear alpha-olefins having from 3 to 12 carbon atoms ormaleic anhydride.
 11. A solid shaped article according to claim 1,wherein the natural wax is selected from carnauba wax, candelilla wax,palm wax, lignite wax, ozokerite, lardaceine, ceresine wax and Chinawax.
 12. A solid shaped article according to claim 1, wherein the waxcomprises compounds selected from saturated hydrocarbons having from 25to 31 carbon atoms, saturated alcohols having from 25 to 31 carbonatoms, saturated monocarboxylic acids having from 25 to 31 carbon atoms,esters obtained from the said alcohols and monocarboxylic acids andhaving from 50 to 62 carbon atoms, and their mixtures.
 13. A solidshaped article according to claim 1, wherein the cushioning beads havean average particle size of 0.5 to 2.0 mm.
 14. A method according toclaim 5, wherein the microcrystalline hydrocarbon wax or natural wax hasa dynamic viscosity at 98.9° C. (DIN 52007) greater than or equal to 2mPa.s and/or a congealing point between 50° C. and 90° C.
 15. A methodaccording to claim 5, wherein the microcrystalline hydrocarbon wax ornatural wax comprises a mixture of 30 to 90% by weight of linearhydrocarbons and 10 to 70% by weight of branched hydrocarbons.
 16. Amethod according to claim 5, wherein the distribution of molecular chainlengths within the microcrystalline hydrocarbon wax or natural wax issuch that less than 6% of the molecules have less than 25 carbon atoms,6 to 50% of the molecules have 25 to 29 carbon atoms, 20 to 45% of themolecules have 30 to 34 carbon atoms and 7 to 70% of the molecules haveat least 35 carbon atoms.
 17. A method according to claim 5, wherein themicrocrystalline hydrocarbon wax is a product of catalyticpolymerization of ethylene or copolymerization of ethylene with minoramounts of linear alpha-olefins having from 3 to 12 carbon atoms ormaleic anhydride.
 18. A method according to claim 5, wherein the naturalwax is selected from carnauba wax, candelilla wax, palm wax, lignitewax, ozokerite, lardaceine, ceresine wax and China wax.
 19. A methodaccording to claim 5, wherein the wax comprises compounds selected fromsaturated hydrocarbons having from 25 to 31 carbon atoms, saturatedalcohols having from 25 to 31 carbon atoms, saturated monocarboxylicacids having from 25 to 31 carbon atoms, esters obtained from the saidalcohols and monocarboxylic acids and having from 50 to 62 carbon atoms,and their mixtures.
 20. A method according to claim 1, wherein over 98%of the molecules of the microcrystalline hydrocarbon wax or natural waxhave a molecular chain length ranging from 20 to 75 carbon atoms.
 21. Inan article containing a biologically active ingredient and a hydrocarbonwax or natural wax, the improvement wherein: said article contains thebiologically active ingredient in the form of biologically activeingredient-loaded beads of a size of about 0.5 to 2 mm with a brittlecoating, said article further comprises biologically inactive cushioningbeads of a size of about 0.5 to 2 mm with at least one compressiblecushioning component comprising a microcrystalline hydrocarbon wax or anatural wax, the said wax being at least 30% by weight of thebiologically inactive cushioning beads, and up to 70% by weight ofanother biologically inactive compressible cushioning component orpharmaceutically acceptable excipient, and wherein the weight ratio ofthe biologically inactive cushioning beads to the coated biologicallyactive ingredient-loaded beads is between 30:70 and 70:30.
 22. A methodfor treating a plant in need of a biological treatment or a mammal inneed of a medication by bringing the said plant into contact with anefficient amount of a biologically active ingredient or by administeringto said mammal an efficient amount of said medication containing abiologically active ingredient, including providing the biologicallyactive ingredient in the form of biologically active ingredient-loadedbeads of a size of about 0.5 to 2 mm with a brittle coating, providingbiologically inactive cushioning beads of a size of about 0.5 to 2 mmwith at least one compressible cushioning component comprising amicrocrystalline hydrocarbon wax or a natural wax, the said wax being atleast 30% by weight of the biologically inactive cushioning beads, andup to 70% by weight of another biologically inactive compressiblecushioning component or pharmaceutically acceptable excipient, and70:30, compressing beads wherein the weight ratio of the biologicallyinactive cushioning beads to the coated biologically activeingredient-loaded beads is between 30:70 and 70:30 to form a solidshaped compressed article, and bringing the solid shaped compressedarticle into contact with said plant or mammal.
 23. A solid shapedarticle according to claim 1, wherein the biologically activeingredient-loaded beads are formed by extrusion-spheronization.
 24. Ashaped article according to claim 5, wherein the biologically activeingredient-loaded beads are made by extrusion-spheronization.
 25. Asolid shaped article according to claim 21, wherein the biologicallyactive ingredient-loaded beads are formed by extrusion-spheronization.26. A solid shaped article according to claim 22, wherein thebiologically active ingredient-loaded beads are made byextrusion-spheronization.